Martha Denckla - US grants

learning disorders; developmental neurobiology;

This application for support of years 11 through 15 of the Mental Retardation Research Center (MRRC) at the Kennedy Krieger Institute and John Hopkins University is submitted in response to RFA HD-97-003. The MRRC consists of an administrative core (Core A) and five research cores (Cores B, C, D, E, and F). The Core A (Administrative), provides overall management and organizational support to the Center, operates overall management and organizational support to the Center, operates the educational component (lectures and seminars) and links users to biostatistical services. Core B (Genetics) provides centralized tissue culture, amino acid, organic acid analyses, standard and molecular cytogenetics, specialized molecular genetics (DNA and RNA analyses) and bioinformatics. Core C (Neuroscience) provides synaptic neurochemistry (focusing on histology imaging and high performance liquid chromatography) and lipid biochemistry (including general mass spectrometry services). Core D (Animal Facilities) provides animal (mostly mouse) models by assessing genetically altered mutants or stock strains in maintaining them disease-free. Core E (Neuroimaging) provides for acquisition and quantitative analysis of data derived from functional, morphometric, and spectroscopy MR imaging and positron emission tomography. Core F (Behavior Science) offers training of subjects for cooperation with research protocols, selection and administration of standardized tests (developmental, cognitive and functional), direct observations of behavior, and design of activation paradigms for fMRI. The core units serve 62 projects representing current direct annual NIH support totalling over 14 million dollars. The program addresses 14 of the 21 priority areas set forth in RFA HD-87-003, featuring interdisciplinary collaboration and a theme, brain mechanisms whereby genotypes result in specific cognitive and behavioral phenotypes of mental retardation or developmental disability.

DESCRIPTION (provided by applicant): There is evidence that girls with ADHD differ from boys with ADHD most strikingly in 1) academic and social-emotional and 2) neurobiological features. Building upon previous research experience concerning neurobiological features of boys with ADHD, this proposal focuses on 2) neurobiology of girls with ADHD, with plans to derive data from quantitative volumetric/anatomic magnetic resonance imaging (aMRI) and assessments of executive behaviors, both motor/oculomotor and cognitive. To take gender into account, girls with ADHD will be compared with control girls as well as boys with and without ADHD. The age range for all 200 subjects (50 in each group) will be 9.0 through 11.5 years; in addition, even at this young age, Tanner staging will be taken into consideration. Anatomic MRI regions of interest will be frontal lobe, basal ganglia, and cerebellum. It is hypothesized that girls with ADHD will differ from boys with ADHD at the levels of frontal lobe (showing anomalous asymmetry only), and at the level of the basal ganglia (showing symmetrically smaller total caudate and globus pallidus volumes) while sharing with boys total cerebral and posterior inferior vermis reductions. Behavioral tasks, motor/oculomotor as well as cognitive, will be categorized into inhibitory control, response preparation, and working memory, functions thought to represent parallel frontostriatal and cerebellar interlocking circuits. It is hypothesized that girls with ADHD will be relatively more impaired in terms of response preparation and working memory than in terms of inhibition, a profile opposite to that of boys with ADHD. Gender-by-subtype interactions with respect to aMRI and behavioral datasets and the impact of emotional symptoms will be analyzed. Brain-behavior relationships as influenced by gender (modified by covariates as noted above) will be interpreted in terms of a neurodevelopmental model of ADHD.

DESCRIPTION [provided by applicant]: This application for continued support of Years 16 through 20 of the Mental Retardation/Developmental Disabilities Research Center (MRDDRC) at the Kennedy Krieger Institute and Johns Hopkins University is submitted in response to RFA HD-02-014. The MRDDRC consists of the Administrative Core (Core A) with a research subdivision and five research cores (Cores B, C, D, E, and F). Core A (Administration), provides overall leadership, management, and organizational support to the Center, operates the educational component (lectures and seminars), and links users to biostatistical services (a research subdivision). Core B (Genetics) provides centralized tissue culture, amino acid/organic acid analyses, standard and molecular cytogenetics, specialized molecular genetics (DNA and RNA analyses) microarrays and bioinformatics. Core C (Neuroscience) provides synaptic neurochemistry (focusing on histology imaging and high performance liquid chromatography) and lipid biochemistry (lipid metabolism, fatty acid analysis, and mass spectrometry services). Core D (Motion Analysis) provides quantitative computer-assisted methods of documenting gaits, reaching, and learning behaviors within the motor domain. Core E (Neuroimaging) provides for acquisition and quantitative analysis of data derived from functional, volumetric, diffusion tensor, and spectroscopic MR imaging, and Core F (Behavioral Science) offers training of subjects for cooperation with research protocols, selection and administration of standardized tests (developmental, cognitive, and functional), direct observations of behavior, and design of activation paradigms for fMRI.

female; cognition; neurobiology; child psychology; attention deficit disorder; middle childhood (6-11); gender difference; psychomotor function; male; short term memory; impulsive behavior; eye movements; cerebellum; basal ganglia; frontal lobe /cortex; emotions; patient oriented research; behavior test; magnetic resonance imaging; human subject; behavioral /social science research tag; clinical research;

[unreadable] DESCRIPTION (provided by applicant): Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent disorder that can cause substantial impairment in family/social relationships and the ability to succeed in school and occupation; yet, fundamental aspects of the neurobiology of ADHD remain poorly understood. Anomalous motor development is a consistent, but infrequently studied characteristic observed with ADHD that can provide insight into the neurologic basis of the disorder. Children with ADHD fail to meet age-norms on timed repetitive and sequential movements and manifest a greater amount of motor overflow than age-matched controls. These findings, which can accurately distinguish ADHD children from normal controls and children with other neuropsychiatric disorders, suggest that ADHD is associated with abnormalities of motor cortex inhibitory systems. Functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) can localize and quantify inhibition within the motor cortex and thus are particularly suited to study motor inhibition in ADHD. We hypothesize that the neuromotor anomalies present in children with ADHD are associated with deficient intracortical and interhemispheric inhibition of the motor cortex. This hypothesis is consistent with studies suggesting that the central deficit of ADHD is a failure to inhibit or delay a behavioral response. Our preliminary studies using both fMRI and TMS suggest that abnormalities of motor cortex inhibition are present in children with ADHD. The overall goal of this project is to investigate the neurologic basis of motor anomalies associated with ADHD. We propose three specific aims. In the first aim we will measure overflow movements using electromyography (EMG) and accelerometry, which will allow us to detect meaningful correlations between overflow measurements and neurophysiologic and imaging data. The second aim will focus on examining motor cortex inhibition using TMS. The third aim will assess patterns of fMRI activation during simple finger movements, including activation patterns associated with overflow movements. We will then examine the relationship between abnormalities of cortical inhibition and measures of hyperactivity and inattention. The data from these studies will yield critical insights into the neurobiological basis of ADHD and will also set the stage for future development of more effective therapies for this population. [unreadable] [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): The overarching goal of this Research Center is to examine the reading disabilities (RDs) present in children grades 3-8, including classification, identification, treatment, prevalence, neurocognitive characteristics, as well as the influence of comorbidities (Attention Deficit Hyperactivity Disorder; ADHD) on reading. While much is known about early reading development and disorders, there has been much less examination of reading and RDs past the early elementary grades. Therefore, there is a critical gap in knowledge about what it takes for a reader to be able to effectively glean information - or learn - from text, even though this is arguably the most important skill needed to achieve academic success after the 3rd grade. Our Research Center seeks to fill this critical gap in knowledge by bringing together a diverse and talented set of researchers and institutions (Kennedy Krieger Institute, Haskins Laboratories, Educational Testing Services (ETS), and University of Maryland) to conduct inter-related projects, the findings from which will allow us to gain a deep understanding of the neurobiological and behavioral processes that influence reading achievement past the early elementary grades. Our overarching hypothesis is that RDs past the early elementary years are heterogeneous in nature, caused by both "bottom up" and "top down" processes. Within this context, we propose projects that I) examine the neurobiological and behavioral development of word level efficiency, the relationship between word-level and text-level fluency and comprehension, and the influence of different textual demands upon comprehension; II) examine the validity of RTI as a way of identifying children with RDs, and to determine if there are neurocognitive indicators that predict intervention responsiveness; III) determine how the cognitive aspects of ADHD (processing speed, working memory) influence reading comprehension; and IV) to determine the prevalence of different subtypes of RDs by building upon the knowledge gained from Projects I, II, and III, as well as analyses of extant datasets. Thus, within the framework of Project IV, the projects of the Research Center converge in an endeavor that will have significant public health value. Knowing the common subtypes of RDs at what age, as well as the influence of ADHD, will help reveal what the instructional emphasis (es) should be for the older children in our nation, including what risk factors teachers should be looking for. [unreadable] [unreadable] [unreadable]

Introduction This Core (A) of the Research Center will consist of the Director (the Principal Investigator of the entire Center), the Associate Director, Laurie Cutting, Ph.D., a Financial/Budget Administrator, a Program Administrator, and an Information Specialist. Through interlocking and overlapping relationships with the Mental Retardation Developmental Disabilities Research Center (MRDDRC), no statistical key personnel are represented directly within this Core;and the services of the expert statistics consultant, Dr. Scott Zeger, are financed as a function of MRDDRC. General Kennedy Krieger Institute support is provided for the Financial/Budget Administrator. Thus, there are major aspects of Core A that are available to Core A (as "central user" on behalf of this Research Center) that are services of the MRDDRC. How this has evolved will be described in the section on Organization.